Neuroligin binds its presynaptic ligand neurexin to modify synaptic functions in the brain. Disruption in the neuroligin signaling pathway is associated with devastating disorders like autism, schizophrenia, fragile X syndrome and others. However, little is known about how neuroligin signaling modifies neural circuit function and animal behavior. A complete understanding of this process requires thorough characterization of neural circuits and their components along with the ability to measure and more importantly perturb their activity. Invertebrate circuits with their well-defined neuroanatomy and quantitative behaviors are ideal to decipher the neuroligin signaling mechanisms underlying complex outputs. The nematode, Caenorhabditis elegans, with its nervous system comprising of just 302 neurons with identified connections and highly conserved synaptic machinery provides an unique opportunity to analyze genes, cells and circuits regulating complex behaviors. The Chalasani lab has identified a novel neuropeptide-based communication between the AWC (sensing odors) and ASE (sensing salt) neurons. Surprisingly, a C. elegans mutant for the homolog of human neuroligin that is associated with autism in patients shows severe defects in behaviors regulated by the neuropeptide communication between AWC and ASE sensory neurons. Moreover, they show that wild-type human neurolign cDNA, but not two autism-associated gene variants can rescue the nlg-1 behavioral defects. These results suggest that neurolign signaling is conserved between worms and humans. They propose to identify the neuropeptides and receptors that underlie the novel AWC-ASE communication (Aim 1). They will also test the hypothesis that post-synaptic NLG-1 modifies the neuropeptide signaling between AWC and ASE neurons. Moreover, they will test worm homologs of human disease-associated gene variants and neurexin in influencing neural circuit functions (Aim 2). Finally, they will modify an automated imaging platform to perform novel neural activity based genetic screens and identify components of the NLG-1 signaling pathway (Aim 3). These studies will clarify how neural circuits integrate information at the level of synapses, neural circuits and whole organisms and identify candidates relevant to human disease.

Public Health Relevance

Disrupting neuroligin signaling in the brain leads to devastating disorders such as autism, schizophrenia, fragile X and others. We propose to use a simple well-defined model with conserved neuroligin signaling to dissect how this pathway influences brain functions. We aim to use our model to develop new early diagnostic tools and identify new targets for therapeutic intervention in these diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH096881-01A1
Application #
8438368
Study Section
Special Emphasis Panel (ZRG1-MDCN-P (57))
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2012-12-01
Project End
2017-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
1
Fiscal Year
2013
Total Cost
$477,449
Indirect Cost
$211,500
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Leinwand, Sarah G; Chalasani, Sreekanth H (2014) From genes to circuits and behaviors: Neuropeptides expand the coding potential of the nervous system. Worm 3:e27730
Lau, Hiu E; Chalasani, Sreekanth H (2014) Divergent and convergent roles for insulin-like peptides in the worm, fly and mammalian nervous systems. Invert Neurosci 14:71-8
Leinwand, Sarah G; Chalasani, Sreekanth H (2013) Neuropeptide signaling remodels chemosensory circuit composition in Caenorhabditis elegans. Nat Neurosci 16:1461-7